Dr. Feroz R. Papa is an endocrinologist, strongly committed to an academic career as an independent investigator in (-cell molecular biology. His specific interest is the role of endoplasmic reticulum (ER) stress in development of diabetes mellitus type 2 (DM2). Accordingly, he has initiated a postdoctoral fellowship in the lab of Dr. Peter Walter, in the Dept. of Biochemistry and Biophysics at UCSF, studying the Unfolded Protein Response (UPR), a homeostatic mechanism through which eukaryotic cells adjust to ER stress. ER stress occurs when there is an imbalance between the load of client proteins undergoing maturation in the ER lumen and the capacity of the ER to process this load. Pathophysiological conditions provoking ER stress include anoxia, nutrient deprivation, and polypeptide mutations, which result in protein misfolding. The UPR remodels the environment of the ER to respond to ER stress through two mechanisms: 1) a transcriptional upregulation of genes encoding ER chaperones, enzymatic activities, and structural ER components, and 2) a global translational halt, which reduces the load of ER client proteins. The ER-transmembrane kinase/endoribonuclease Ire1alpha is the sensor for the transcriptional arm of the UPR, and the ER-transmembrane elF-2alpha kinase Perk is the sensor for the translational arm. Dr. Papa is proposing a research program which will address the hypothesis that modulating the UPR, in real time using small molecule effectors, can influence the function of beta-cells, and ultimately their survival. He will address this hypothesis through three specific aims. First, using a chemical-genetic strategy, he will sensitize Ire1alpha by gene targeting of IRE1alpha to a cell-permeable ATP analog, 1-NM PP1, which he has demonstrated is a permissive co-factor for signaling by sensitized Ire1 in yeast. Beta-cell-specific gene targeting would render this tissue unable to signal the transcriptional arm of the UPR in the absence of 1NM-PP1 Second, similar gene targeting of PERK will be conducted, conferring pharmacological conditionality on the translational arm of the UPR. Third, the biological consequences of these manipulations on beta-cells will be studied in these knock-in mutants, and in the genetic background of three other mouse mutants which develop DM2 as a consequence of unchecked ER stress: Akita, hlAPP, and perk-/-. Together this work promises to yield important insights into how professional secretory tissues (including, but not limited to beta-cells) adapt to physiological and pathophysiological stresses. Dr. Papa will conduct this work in the Dept. of Biochemistry and Biophysics at UCSF under the mentorship of Dr. Peter Walter, and in collaboration with Dr. Robert Farese, Jr. in the Gladstone Institute of Cardiovascular Disease, and Dr. Kevan Shokat in the Department of Cellular and Molecular Pharmacology. The UCSF Department of Medicine is fully committed to Dr. Papa's career development, and will make all necessary resources available to facilitate the success of the project.